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A hemifused complex is the hub in a network of pathways to membrane fusion
bioRxiv - Biophysics Pub Date : 2022-02-15 , DOI: 10.1101/2021.06.20.449175
Jason M. Warner , Dong An , Benjamin S. Stratton , Ben O’Shaughnessy

Membrane fusion is a critical step for many essential processes, from neurotransmission to fertilization. For over 40 years protein-free fusion driven by calcium or other cationic species has provided a simplified model of biological fusion, but the mechanisms remain poorly understood. Cation-mediated membrane fusion and permeation are essential in their own right to drug delivery strategies based on cell-penetrating peptides or cation-bearing lipid nanoparticles. Experimental studies suggest calcium drives anionic membranes to a hemifused intermediate which constitutes a hub in a network of pathways, but the pathway selection mechanism is unknown. Here we develop a mathematical model that identifies the network hub as a highly dynamical hemifusion complex. Multivalent cations drive expansion of this high tension hemifusion interface between interacting vesicles during a brief transient. The fate of this interface determines the outcome, either fusion, dead-end hemifusion or vesicle lysis. The model reproduces the unexplained finding that calcium-driven fusion of vesicles with planar membranes typically stalls at hemifusion, and we show the equilibrated hemifused state is a novel lens-shaped complex. Thus, membrane fusion kinetics follow a stochastic trajectory within a network of pathways, with outcome weightings set by a hemifused complex intermediate.

中文翻译:

半融合复合体是膜融合通路网络中的枢纽

膜融合是从神经传递到受精的许多基本过程的关键步骤。40 多年来,由钙或其他阳离子物种驱动的无蛋白质融合提供了生物融合的简化模型,但其机制仍然知之甚少。阳离子介导的膜融合和渗透对于基于细胞穿透肽或含阳离子脂质纳米颗粒的药物递送策略本身来说是必不可少的。实验研究表明,钙将阴离子膜驱动到构成通路网络中的枢纽的半融合中间体,但通路选择机制尚不清楚。在这里,我们开发了一个数学模型,将网络中心识别为高度动态的半融合复合体。在短暂的瞬态过程中,多价阳离子驱动相互作用的囊泡之间的这种高压半融合界面的扩展。这个界面的命运决定了结果,无论是融合、死端半融合还是囊泡溶解。该模型重现了无法解释的发现,即钙驱动的囊泡与平面膜的融合通常在半融合时停止,我们表明平衡半融合状态是一种新型的透镜状复合物。因此,膜融合动力学遵循路径网络内的随机轨迹,结果权重由半融合复合中间体设定。该模型重现了无法解释的发现,即钙驱动的囊泡与平面膜的融合通常在半融合时停止,我们表明平衡半融合状态是一种新型的透镜状复合物。因此,膜融合动力学遵循路径网络内的随机轨迹,结果权重由半融合复合中间体设定。该模型重现了无法解释的发现,即钙驱动的囊泡与平面膜的融合通常在半融合时停止,我们表明平衡半融合状态是一种新型的透镜状复合物。因此,膜融合动力学遵循路径网络内的随机轨迹,结果权重由半融合复合中间体设定。
更新日期:2022-02-18
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